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Analysis of Pgp/MDR1 activity and molecular response in chronic myelogenous leukemia (CML) cells treated with Imatinib mesylate

Imatinib mesylate (IM) is a specific inhibitor of the BCR-ABL tirosine kinase. The treatment goal of IM in CML is clinical, hematological and molecular remission of the disease. However, we have previously shown that IM treatment could induce multidrug resistance (MDR) where the membrane transporter P glycoprotein (Pgp) decreases treatment success through amplified efflux of IM. In order to elucidate the mechanism of MDR induction by evaluating it through a longer period, we observed observed the effect of IM monotherapy (400-600mg/day), and the variations in the activity of Pgp pump and then compared them with molecular response kinetics. Pgp activity of bone marrow and peripheral blood cells MDR was observed in 14 CML patients with flow cytometric rhodamine dye efflux test and the result was expressed as the ratio of minimal and real pump activity (RMF, rang of values 0, 6-1, 3) where RMF>1 expressed the elevated activity. The kinetics of molecular response was measured by quantitative RT-PCR method (TaqMan) and the results were divided in 4 rangs: R1 complete molecular remission (PCR neg) in 5 (35%) patients, R2 (major response in one (7%), R3 (minor response in 3 (22%) and with weak response or without any response at all in 5 (35%) patients in R4 range. All R1 patients had low Pgp activity whereas the greatest activity increase was observed in R4. The correlation between MDR and RT-PCR was determined and confirmed with rang correlation (rs=0, 66 ; p<0, 001). We conclude that rhodamine test of Pgp activity has clinical value and correlates with the disease activity measured by molecular level of oncogene BCR-ABL chimeric genes.

multidrug resistence; Pgp; MDR; CLL

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